First step towards a consensus strategy for multi-locus diagnostic testing of imprinting disorders

Area of Science:

• Genetics
• Epigenetics
• Molecular Biology

Background:

• Imprinting disorders arise from parent-specific gene expression, impacting growth, development, metabolism, and cancer risk.
• These disorders result from genetic or epigenetic alterations, including coding sequence changes, copy number variations, uniparental disomy, or imprinting defects.
• Clinical presentation can be heterogeneous, involve multiple imprinted loci, and challenge traditional single-locus diagnostic methods.

Purpose of the Study:

• To evaluate how different diagnostic testing strategies (single-locus vs. multi-locus) impact diagnostic outcomes for imprinting disorders.
• To explore the potential of multi-locus testing to enhance diagnostic efficiency and identify unforeseen diagnoses.
• To analyze the experiences of diagnostic laboratories in identifying imprinting disorders.

Main Methods:

• Data collection from 11 international laboratories involving 16,364 individuals across eight imprinting disorders.
• Analysis of diagnostic outcomes based on single-locus and/or multi-locus testing strategies.
• Review of molecular changes detected in specific disorders like Silver-Russell syndrome and Beckwith-Wiedemann syndrome.

Main Results:

• In Silver-Russell syndrome testing, 115 out of 731 individuals with classical changes had unexpected diagnoses, including atypical molecular alterations or multi-locus imprinting disorders.
• The molecular findings in Beckwith-Wiedemann syndrome and other imprinting disorders varied depending on the laboratory's testing approach.
• Diagnostic yield in real-world laboratory settings was lower than in clinically well-characterized cohorts.

Conclusions:

• Multi-locus testing offers an optimized diagnostic approach for both common and rare imprinting disorders.
• The findings highlight the need for systematizing clinical and molecular data collection in diagnostic laboratories.
• Implementing multi-locus strategies can increase the detection rate of complex and atypical imprinting defects.